Hyaluronan-Mediated CD44 Signaling Activates Cancer Stem Cells in Head and Neck Cancer

Abstract

Head and neck squamous cell carcinoma (HNSCC) is an aggressive disease associated with high morbidity and mortality. Hyaluronan (HA), a major component in the extracellular matrix (ECM) of most mammalian tissues, is accumulated in many types of tumors including HNSCC and is also highly concentrated in stem cell niches. The unique HA-enriched microenvironment appears to be involved in both the self-renewal and differentiation of human cancer stem cells (CSCs). HA binds to a ubiquitous, abundant, and functionally important family of cell surface receptors, defined by CD44. This article reviews the current evidence for the existence of a subpopulation of CD44-expressing cancer stem cells (CSCs) in HNSCC. A special emphasis is placed on HA/CD44-dependent expression of stem cell transcription factors (Nanog, OCT4, and SOX2), cell signaling, and oncogenic microRNA activation, and how the action of these factors supports CSC functions including formation of spheroid cells, self-renewal, clone formation, and chemotherapeutic drug resistance. All of these events are known to contribute to CSC-associated tumor initiation and HNSCC progression in head and neck cancer. HA/CD44-mediated CSC signaling pathways are emerging as important structural and functional tumor markers. In addition, these proteins may be valuable as drug targets in strategies to inhibit tumor cell growth, survival, and invasion/metastasis as well as to overcome chemoresistance in HNSCC.